Engineered Scaffolds for Intervertebral Disc Repair and Regeneration and for Articulating Joint Repair and Regeneration

ABSTRACT

Methods for the engineering and preparation of intervertebral disc repair scaffolds and articulating joint repair scaffolds are disclosed. The methodology utilizes either magnetic resonance images or combined magnetic resonance and computed tomography images as a template for creating either the intervertebral scaffold or the joint repair scaffold (e.g., osteochondral scaffold) with fixation to the underlying bone. The disc scaffold design may include an outer annulus that may contain desired structures and a central nucleus pulposus region that could either contain a designed microstructure or a contained hydrogel. The osteochondral scaffold may include a bone compartment interface with a cartilage compartment. The bone compartment may interface with a cutout portion of the bone through fixation components. Different microstructure designs may be created for the bone and cartilage compartment to represent desired mechanical and mass transport properties. The microstructure controls elastic and permeability property distribution within the scaffold.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 11/927,281 filed Oct. 29, 2007, which claims priority from U.S.Provisional Patent Application No. 60/855,234 filed Oct. 30, 2006.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under grant number RO1DE 13608 and grant number AR 052893 awarded by the National Institutesof Health. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to biomaterial scaffolds, and more particularlyto biomaterial scaffolds for intervertebral disc repair and/orregeneration and biomaterial scaffolds for articulating joint repairand/or regeneration.

2. Description of the Related Art

It is reported in U.S. Patent Application Publication No. 2003/0069718and corresponding U.S. Pat. No. 7,174,282 that biomaterial scaffolds fortissue engineering perform three primary functions. The first is toprovide a temporary function (stiffness, strength, diffusion, andpermeability) in tissue defects. The second is to provide a sufficientconnected porosity to enhance biofactor delivery, cell migration andregeneration of connected tissue. The third requirement is to guidetissue regeneration into an anatomic shape. It is further noted that thefirst two functions present conflicting design requirements.Specifically, increasing connected porosity to enhance cell migrationand tissue regeneration decreases mechanical stiffness and strength,whereas decreasing porosity increases mechanical stiffness and strengthbut impedes cell migration and tissue regeneration.

U.S. 2003/0069718 provides a design methodology for creating biomaterialscaffolds with internal porous architectures that meet the need formechanical stiffness and strength and the need for connected porosityfor cell migration and tissue regeneration. The design methods of U.S.2003/0069718 combine image-based design of pore structures withhomogenization theory to compute effective physical property dependenceon material microstructure. Optimization techniques are then used tocompute the optimal pore geometry. The final optimized scaffold geometryvoxel topology is then combined with a voxel data set describing thethree dimensional anatomic scaffold shape which may be obtained bymagnetic resonance (MR) images or combined MR and computed tomography(CT) images. Density variations within the anatomic scaffold voxeldatabase are used as a map to guide where different optimized scaffoldvoxel topologies are substituted. The final voxel representation of theanatomically shaped scaffold with optimized interior architecture isthen converted automatically by software into either a surfacerepresentation or wire frame representation for fabrication of thescaffold by way of solid free form fabrication or casting.

While the advances of U.S. 2003/0069718 have significantly improved thedesign of biomaterial scaffolds for tissue engineering, there is still aneed for further advances in this technology to provide for even moreoptimized biomaterial scaffolding and tissue generation systems.

SUMMARY OF THE INVENTION

The present invention provides methods for the engineering andpreparation of scaffolding and tissue generation systems for the repairof bone/cartilage composites, including, but not limited to,osteochondral scaffolds/tissue repair systems for the tibial plateau,proximal femoral head, acetabulum, humeral head, and intervertebralspinal disc repair and regeneration. The methodology utilizes eithermagnetic resonance images or combined magnetic resonance and computedtomography images as a template for creating either the intervertebralscaffold as well as the fixation for the scaffolding into adjacentvertebral bodies or the osteochondral scaffold with fixation to theunderlying bone.

The disc scaffold design may include an outer annulus that may containdesired porous structures and a central nucleus pulposus region thatcould either contain a designed porous microstructure or a containedhydrogel or other bioactive agent(s). Instrumentation for surgicalplacement is also included. The scaffolding has designed microstructurethat controls elastic and permeability property distribution within theintervertebral zone.

The osteochondral scaffold may include a bone compartment interface witha cartilage compartment. The bone compartment may interface with acutout portion of the bone through fixation components such as pegs andscrews and the like.

Different microstructure designs may be created for the bone andcartilage compartment to represent desired mechanical and mass transportproperties.

Advantages of the method of the invention include the ability to createdesigned microstructures that can mimic intervertebral load carryingcapability, to provide directed nutrients to seeded/migrated cells inthe disc, and the capability of creating disc structures that can regrownatural tissue. This provides a potential advantage over artificialdiscs, which as synthetic materials are subject to wear and fatiguefailure. Regrowth of a new disc would provide a natural tissue thatcould remodel in response to applied loads and would be subject to thewear and fatigue problems of synthetic materials. In addition, thecapability of creating designed scaffolding would provide the necessaryload bearing capability via designed elasticity and permeability fortissue engineering an intervertebral disc that non-designed scaffoldscould not provide. In addition, if the designed scaffolding is used forfusion, it could provide load bearing capability that would eliminatethe need for some or all of the hardware needed for current interbodyfusion techniques.

For the osteochondral scaffold, advantages include the ability to designa separate bone/cartilage interface, and more importantly, the abilityto design these bone and cartilage compartments to have desiredeffective mechanical and mass transport properties. In addition, theosteochondral scaffolds could have virtually any interface withsurrounding tissue or for surgical fixation.

For the total joint interface, advantages again include the ability tohave control over the designed microstructure interface, giving itdesired interface elasticity properties and the ability to controlgeometric thickness.

In one aspect of the invention, there is provided a method for designinga tissue scaffold for generating tissue in a patient. In the method, afirst set of databases is created representing a plurality of porousmicrostructure designs for the scaffold in image based format. A seconddatabase is created representing scaffold exterior geometry desired toreplace the native tissue in the patient in image based format. A thirddatabase is created representing scaffold external fixation structure.Then, the first set of databases representing the desired microstructuredesigns and the second database and the third database are merged intoan image-based design of the scaffold. The image-based design may thenbe converted to a fabrication geometry such as surface representation orwireframe representation.

In one form, the scaffold external fixation structure is designed to beporous, and is designed to include at least one projection extendingaway from the scaffold. Example projections are a peg or a spike or aplate. The projection can be designed to include fastening meansselected from threads and/or throughholes. In one embodiment, thescaffold is designed for intervertebral disc repair. In anotherembodiment, the scaffold is designed for articulating joint repair. Inyet another embodiment, the scaffold is designed for total jointreplacement.

The scaffold external fixation structure can be designed to include atleast one projection extending away from the scaffold, and at least onemarking including a tracer that provides enhanced visibility via amedical imaging device can be placed on the at least one projection. Thescaffold external fixation structure can be designed to include at leastone projection extending away from the scaffold, and at least oneradiopaque marking that provides enhanced visibility via a fluoroscopecan be placed on the at least one projection. The scaffold can bedesigned to include a region of no material or radiolucent material suchthat the region forms an imaging window for enhanced visibility throughthe imaging window via a medical imaging device. The scaffold externalfixation structure can be designed to include at least one projectionextending away from the scaffold, and at least one marking for alignmentduring implantation can be placed on the at least one projection.

In another aspect of the invention, there is provided a method fordesigning an intervertebral disc scaffold. In the method, a first set ofdatabases is created representing a plurality of porous microstructuredesigns for the scaffold in image based format. A second database iscreated representing scaffold exterior geometry desired to replace thenative disc in the patient in image based format. Then, the first set ofdatabases representing the desired microstructure designs are mergedwith the second database into an image-based design of the scaffold. Theimage-based design can be converted to a fabrication geometry. Thesecond database can represent an intervertebral space to be occupied bythe scaffold.

In one form, the image-based design of the scaffold can be designed toinclude an outer annulus having a first designed porous microstructure,and the image-based design of the scaffold can be designed to include acentral region having a second designed microstructure. In another form,the image-based design of the scaffold can be designed to include anouter annulus having a first designed porous microstructure, and theimage-based design of the scaffold can be designed to include a centralregion designed for containing a biocompatible material. At least one ofthe microstructure designs can be a wavy fiber design. In one form, theimage-based design of the scaffold is designed to include spherical orelliptical pores.

The scaffold can be designed to include at least one projection, such asa plate, peg or spike, extending away from the scaffold, and at leastone marking including a tracer that provides enhanced visibility via amedical imaging device can be placed on the at least one projection. Thescaffold can be designed to include at least one projection extendingaway from the scaffold, and at least one radiopaque marking thatprovides enhanced visibility via a fluoroscope can be placed on the atleast one projection. The scaffold can be designed to include at leastone projection extending away from the scaffold, and at least onemarking for alignment during implantation can be placed on the at leastone projection. The scaffold can be designed to include a region of nomaterial or radiolucent material such that the region forms an imagingwindow for enhanced visibility through the imaging window via a medicalimaging device.

In yet another aspect of the invention, there is provided a method fordesigning an osteochondral scaffold for replacing native tissue in apatient. In the method, a first set of databases is created representinga plurality of porous microstructure designs for the scaffold in imagebased format. A second database is created representing scaffoldexterior geometry desired to replace the native tissue in the patient inimage based format. The first set of databases representing the desiredmicrostructure designs are merged with the second database into animage-based design of the scaffold that includes a bone region designedto have a first physical or biochemical property and a cartilage regiondesigned to have a second physical or biochemical property. At least oneof the microstructure designs can be a wavy fiber design. The boneregion can be designed to have a pore structure different from a porestructure of the cartilage region. The cartilage region can be designedto include spherical or elliptical pores. The bone region can bedesigned to allow greater mass transport than the cartilage region.

The first physical or biochemical property can be a mechanical property(such as elasticity), and the second physical or biochemical propertycan be a mechanical property (such as elasticity). The first physical orbiochemical property can be a mass transport property (such aspermeability), and the second physical or biochemical property can be amass transport property (such as permeability). The first physical orbiochemical property can be a biochemical property (such as bioactiveagent delivery control), and the second physical or biochemical propertycan be a biochemical property (such as bioactive agent deliverycontrol).

In one embodiment, the first physical or biochemical property can beachieved by coating at least a portion of the bone region with anosteoconductive mineral. In another embodiment, the first physical orbiochemical property can be achieved by coating at least a portion ofthe bone region with an osteoconductive mineral comprising a calciumcompound. In yet another embodiment, the first physical or biochemicalproperty can be achieved by coating at least a portion of the boneregion with an osteoconductive mineral comprising a material selectedfrom hydroxyapatite, calcium-deficient carbonate-containinghydroxyapatite, tricalcium phosphate, octacalcium phosphate, dicalciumphosphate, calcium phosphate, and mixtures thereof. In still anotherembodiment, the first physical or biochemical property can be achievedby coating at least a portion of the bone region with an osteoconductivemineral comprising a plurality of discrete mineral islands. In yetanother embodiment, the first physical or biochemical property can beachieved by coating at least a portion of the bone region with anosteoconductive mineral comprising a substantially homogeneous mineralcoating. In still another embodiment, the first physical or biochemicalproperty can be achieved by coating at least a portion of the boneregion with an osteoconductive mineral and associating a bioactive agentwith the mineral coating. The bioactive agent can be selected from bonemorphogenetic proteins.

In yet another aspect of the invention, there is provided a method fordesigning a joint replacement for a patient. In the method, a first setof databases is created representing a plurality of porousmicrostructure designs for the joint replacement in image based format.A second database is created representing joint replacement exteriorgeometry in image based format. The first set of databases representingthe desired microstructure designs are merged with the second databaseinto an image-based design of the joint replacement that includes a boneregion designed to have a first physical or biochemical property and asurface region designed to have a second physical or biochemicalproperty. At least one of the microstructure designs can be a wavy fiberdesign. The bone region can be designed to have a pore structuredifferent from a pore structure of the surface region. The surfaceregion can be designed to include spherical or elliptical pores. Thebone region can be designed to allow greater mass transport than thecartilage region.

The first physical or biochemical property can be a mechanical property(such as elasticity), and the second physical or biochemical propertycan be a mechanical property (such as elasticity). The first physical orbiochemical property can be a mass transport property (such aspermeability), and the second physical or biochemical property can be amass transport property (such as permeability). The first physical orbiochemical property can be a biochemical property (such as bioactiveagent delivery control), and the second physical or biochemical propertycan be a biochemical property (such as bioactive agent deliverycontrol).

In one embodiment, the first physical or biochemical property can beachieved by coating at least a portion of the bone region with anosteoconductive mineral. In another embodiment, the first physical orbiochemical property can be achieved by coating at least a portion ofthe bone region with an osteoconductive mineral comprising a calciumcompound. In yet another embodiment, the first physical or biochemicalproperty can be achieved by coating at least a portion of the boneregion with an osteoconductive mineral comprising a material selectedfrom hydroxyapatite, calcium-deficient carbonate-containinghydroxyapatite, tricalcium phosphate, octacalcium phosphate, dicalciumphosphate, calcium phosphate, and mixtures thereof. In still anotherembodiment, the first physical or biochemical property can be achievedby coating at least a portion of the bone region with an osteoconductivemineral comprising a plurality of discrete mineral islands. In yetanother embodiment, the first physical or biochemical property can beachieved by coating at least a portion of the bone region with anosteoconductive mineral comprising a substantially homogeneous mineralcoating. In still another embodiment, the first physical or biochemicalproperty can be achieved by coating at least a portion of the boneregion with an osteoconductive mineral and associating a bioactive agentwith the mineral coating. The bioactive agent can be selected from bonemorphogenetic proteins.

In still another aspect of the invention, there is provided anintervertebral disc repair and/or regeneration scaffold. The scaffoldincludes a central core shaped to approximate the nucleus pulposus of anatural intervertebral disc wherein the central core has a first porousmicrostructure. The scaffold further includes an outer annulus shaped toapproximate the annulus fibrosus of a natural intervertebral discwherein the outer annulus is connected to and surrounds the central coreand wherein the outer annulus has a second porous microstructure. In oneembodiment, the central core and the outer annulus have differentelasticity. In another embodiment, the central core and the outerannulus have different permeability. In yet another embodiment, thecentral core and the outer annulus have different bioactive agentrelease properties.

In one form, the central core includes a biocompatible material. Inanother form, the central core includes a hydrogel. In yet another form,the central core includes a bioactive agent. In one embodiment, thebioactive agent is selected from undifferentiated chondrocyte precursorcells from periosteum, mesenchymal stem cells from bone marrow,chondrocytes, sclerosing agents, angiogenesis activators, angiogenesisinhibitors, and mixtures thereof. The central core can comprise wavyfibers.

The scaffold can be formed from biodegradable polymers, biodegradableceramics, non-biodegradable metals, non-biodegradable metal alloys, ormixtures thereof. The scaffold can include at least one markingincluding a tracer that provides enhanced visibility via a medicalimaging device. The scaffold can include at least one radiopaque markingthat provides enhanced visibility via a fluoroscope. The scaffold caninclude a region of no material or radiolucent material such that theregion forms an imaging window for enhanced visibility through theimaging window via a medical imaging device. The scaffold can include atleast one marking for alignment during implantation.

In one embodiment, an osteoconductive mineral coating is disposed on atleast a portion of the scaffold. The osteoconductive mineral coating caninclude a plurality of discrete mineral islands. Alternatively, theosteoconductive mineral coating can include a substantially homogeneousmineral coating. The osteoconductive mineral coating can include acalcium compound. For example, the osteoconductive mineral coating caninclude hydroxyapatite, calcium-deficient carbonate-containinghydroxyapatite, tricalcium phosphate, octacalcium phosphate, dicalciumphosphate, calcium phosphate, and mixtures thereof. A bioactive agentcan be associated with the mineral coating. Example bioactive agent arebone morphogenetic proteins.

These and other features, aspects, and advantages of the presentinvention will become better understood upon consideration of thefollowing detailed description, drawings and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a slice from an external shape design dataset for anintervertebral disc. The internal rings represent the different densityregions for mapping heterogeneous microstructure.

FIG. 2A shows an example of a designed microstructure for scaffoldingwith interconnected cylindrical pores.

FIG. 2B shows an example of a designed microstructure for scaffoldingwith topology optimized microstructure.

FIG. 2C shows an example of a designed microstructure for scaffoldingwith wavy fibered microstructure.

FIG. 3 shows a slice of a designed intervertebral scaffolding with wavyfibered microstructure in the correct anatomic shape. The central regionapproximates the shape of the nucleus pulposus in a naturalintervertebral disc.

FIG. 4 shows an example of an integrated anterior plate fixation on adisc regeneration scaffold. This integrated plating can be used foreither disc regeneration or spinal fusion.

FIG. 5A shows an example of a spiked vertebrae interface on the top ofan intervertebral disc scaffold.

FIG. 5B shows an example of a spiked vertebrae interface on the bottomof the intervertebral disc scaffold of FIG. 5A.

FIG. 6 shows a density map for a tibial plateau.

FIG. 7 shows an example final osteochondral scaffold with desired shapeand microstructure.

FIG. 8 shows the fit of a designed osteochondral scaffold into the wholetibia.

FIG. 9 shows a stem simulating a hip stem with a designed microstructureas an interface for fixation of the stem to surrounding bone.

FIG. 10 shows the steps in engineering a mandibular condyle scaffoldfrom image to fabricated scaffold.

FIG. 11 shows an example of a cervical disc regeneration scaffold withdesigned anterior fixation plate and wavy fiber microstructurefabricated from polycaprolactone (PCL).

Like reference numerals will be used to refer to like or similar partsfrom Figure to Figure in the following description.

DETAILED DESCRIPTION OF THE INVENTION

An intervertebral disc scaffolding according to the invention includes:(i) a designed porous microstructured scaffolding itself, made frombiodegradable polymers (e.g., polycaprolactone), biodegradable ceramics(e.g., calcium phosphate), or non-biodegradable metals or metal alloys(e.g., titanium or titanium alloys), or mixtures thereof, and (ii)fixation structures for integrating the designed intervertebralscaffolding to the adjacent vertebrae. As used herein, a “biodegradable”material is one which decomposes under normal in vivo physiologicalconditions into components which can be metabolized or excreted.

The scaffolding may include a bioactive agent at any desired location inthe scaffold. A “bioactive agent” as used herein includes, withoutlimitation, physiologically or pharmacologically active substances thatact locally or systemically in the body. A bioactive agent is asubstance used for the treatment, prevention, diagnosis, cure ormitigation of disease or illness, or a substance which affects thestructure or function of the body or which becomes biologically activeor more active after it has been placed in a predetermined physiologicalenvironment. Bioactive agents include, without limitation, cells,enzymes, organic catalysts, ribozymes, organometallics, proteins (e.g.,bone morphogenetic proteins), demineralized bone matrix, bone marrowaspirate, undifferentiated chondrocyte precursor cells from periosteum,mesenchymal stem cells from bone marrow, chondrocytes, sclerosingagents, angiogenesis activators, angiogenesis inhibitors, glycoproteins,peptides, polyamino acids, antibodies, nucleic acids, steroidalmolecules, antibiotics, antimycotics, cytokines, fibrin, collagen,fibronectin, vitronectin, hyaluronic acid, growth factors (e.g.,transforming growth factors and fibroblast growth factor),carbohydrates, statins, oleophobics, lipids, extracellular matrix and/orits individual components, pharmaceuticals, and therapeutics.

In areas of the scaffold where bone growth is desired, preferredbioactive agents include, without limitation, bone morphogeneticproteins (such as rhBMP-2,

BMP-2, BMP-4, BMP-7, BMP-14), demineralized bone matrix, bone marrowaspirate, growth and development factor-5 (GDF-5), or platelet richplasma (PRP). In areas of the scaffold where cartilage or fibrous tissuegrowth is desired, preferred bioactive agents include, withoutlimitation, undifferentiated chondrocyte precursor cells fromperiosteum, mesenchymal stem cells from bone marrow, chondrocytes,sclerosing agents (such as surfactants, polidocanol, and sodiummorrhuate), angiogenesis activators, and angiogenesis inhibitors.

The starting point for creating the scaffold may be either a CT image MRimage, a combined MR/CT image, or a digitized cadaver vertebral image.The resulting images provide the external shape and design space for thedisc scaffolding and fixation. These images are stored as densitydistribution within a voxel dataset. In addition, the tissue densitydistribution from the images provides a flag for placing the designedmicrostructure within the global design space. In addition, the globaldensity distribution used as a mapping flag may also be created usingglobal topology optimization. An example of a global densitydistribution of a cross-sectional intervertebral disc image 20 is shownin FIG. 1 wherein the internal rings mark the different density regionsfor mapping heterogeneous microstructure.

A porous microstructure design may be created using the image baseddesign methods described in U.S. Patent Application Publication No.2003/0069718, which is incorporated herein by reference as if fully setforth herein. The steps for performing the scaffold optimization of thepresent invention using the image based design methods described in U.S.Patent Application Publication No. 2003/0069718 are as follows. In step1, the methodology creates unit cell voxel databases. That is, a set ofbase unit cell architectures are created in voxel format ranging overall design parameters. In step 2, the method calculates effectivephysical properties. That is, the method solves homogenization equationsfor each unit cell to calculate effective physical property of thescaffold and the tissue that will grow into the scaffold pores. Themethod can also determine functional dependence of effective stiffness,permeability, and porosity on cell design parameters. In step 3, themethod formulates and solves optimization algorithms of unit cellparameters. That is, the method solves the optimization problem thatwill find the best match of both scaffold and regenerate tissueproperties to naturally occurring tissue properties. The solution givesthe optimal design parameters for the unit cell architecture. In step 4,the method creates an anatomic shape voxel database. That is, the methodcreates a voxel database of the anatomic scaffold shape with differentdensities representing different scaffold architectures. In step 5, themethod merges the anatomic and unit cell architecture data base. Thatis, the method uses image-based Boolean operations to merge the anatomicdata base with density distribution with individual sets of unit celldatabases. In step 6, the method converts the voxel design to a surfaceor wire frame geometry. That is, the method converts the resultingcomplete scaffold design in voxel format to either a triangular facetrepresentation or a wire frame representation that can be used in solidfree form systems. In step 7, the method fabricates the design scaffoldfrom biomaterial using direct or indirect (casting) solid free formtechniques.

In the present invention, the scaffold microstructure will be created toprovide a specified heterogeneous distribution of effective elastic andpermeability properties, designed to provide load bearing capabilitysimilar to a natural human intervertebral disc, along with pathways fornutrient nutrition. The microstructure design may comprise, but is notlimited to, the following: (1) an interconnected system of sphericalpores with varying diameter; (2) an interconnected system of straight orcurved struts with varying diameter; (3) topology optimizedmicrostructures; or (4) wavy fibered structures. FIG. 2A shows anexample of a designed microstructure 22 for scaffolding withinterconnected cylindrical pores. FIG. 2B shows an example of a designedmicrostructure 24 for scaffolding with topology optimizedmicrostructure. FIG. 2C shows an example of a designed microstructure 26for scaffolding with wavy fibered microstructure.

In the microstructure design, the image-based methods as in U.S.2003/0069718 can be used to design an internal architecture optimized tomatch target bone or cartilage Young's moduli. In particular, themodulus ranges for trabecular bone and intervertebral disc that we wouldtarget for fusion and disc repair are: Bone: 30-200 MPa, andIntervertebral Disc: 0.4-10 MPa.

This microstructure may be created by repeating basic unit cell designblocks. These unit cell blocks are also represented as a densitydistribution within a structured voxel dataset. Once the unit celldesigns and global shape template image databases are created, they aremerged using image Boolean operations to create the final design porousmicrostructure scaffolding as described in U.S. Patent ApplicationPublication No. 2003/0069718. A prototype for a designed intervertebraldisc repair and/or regeneration scaffolding is shown in FIG. 3. FIG. 3shows a cross section of a designed intervertebral scaffolding 30 withwavy fibered microstructure 32 in the correct anatomic shape. Thecentral region 34 approximates the shape of the nucleus pulposus in anatural intervertebral disc. The outer region 36 approximates the shapeof the outer annulus fibrosus in a natural intervertebral disc.

The next step in creating the scaffolding is to create a fixationstructure for attaching the disk scaffolding to the adjacent vertebrae.This fixation structure is also created using the same combination ofmicrostructure and global design datasets, as it may be porous to allowbone ingrowth. This fixation may take many forms. One example fixationis a plate attached directly to the scaffold disc. An example of thisfixation is shown in the scaffold 40 of FIG. 4.

In FIG. 4, the wavy fibered microstructure 32 is in the correct anatomicshape for a natural intervertebral disc. A top fixation plate 45includes spaced apart fastener holes 46 a, 46 b and a top centralU-shaped cutaway section 47. A bottom fixation plate 51 includes spacedapart fastener holes 52 a, 52 b, and a bottom central inverted U-shapedcutaway section 53. The wavy fibered microstructure 32 is integral withthe fixation plates 45, 51. When used in intervertebral disc repair, thewavy fibered microstructure 32 of the scaffold 40 would be positioned inthe intervertebral space created by removal of the intervertebral discbetween adjacent vertebrae. Fasteners would be inserted in fastenerholes 46 a, 46 b for anterior attachment to a first upper vertebra, andfasteners would be inserted in fastener holes 52 a, 52 b for anteriorattachment to an adjacent second lower vertebra. The top end surface 54of the wavy fibered microstructure 32 would contact a lower surface ofthe first upper vertebra, and the opposite bottom end surface 55 of thewavy fibered microstructure 32 would contact an upper surface of thesecond lower vertebra. The wavy fibered microstructure 32 therebyprovides mechanical load bearing support between the first uppervertebra and the second lower vertebra.

The vertical dimensions of the wavy fibered microstructure 32 can beadjusted accordingly for various different intervertebral distances.Likewise, the horizontal length of the fixation plates 45, 51 and theirspatial relationship can be varied to ensure proper location of thefastener holes 46 a, 46 b, 52 a, 52 b adjacent the first upper vertebraand the second lower vertebra for securing the scaffold 40 to the firstupper vertebra and the second lower vertebra. By varying the dimensionsof the wavy fibered microstructure 32 and the fixation plates 45, 51,different size scaffolds 40 can be provided for selection by a surgeon.

The scaffold 40 can comprise a porous biocompatible and biodegradable(if desired) porous material selected from polymeric materials, metallicmaterials, ceramic materials and mixtures thereof. In one exampleembodiment, the scaffold 40 is formed from polycaprolactone, abiocompatible and biodegradable polymer. However, other polymers such aspolylactide, polyglycolide, poly(lactide-glycolide), poly(propylenefumarate), poly(caprolactone fumarate), polyethylene glycol, andpoly(glycolide-co-caprolactone) may be advantageous for forming thescaffold 40. As used herein, a “biocompatible” material is one whichstimulates only a mild, often transient, implantation response, asopposed to a severe or escalating response.

An osteoconductive mineral coating can formed on at least a portion ofthe scaffold 40 where bone growth is desired. The osteoconductivemineral coating can comprises a plurality of discrete mineral islands,or the mineral coating can be formed on the entire surface areas of thescaffold 40. In one example form, the osteoconductive mineral coatingcomprises a substantially homogeneous mineral coating. In one exampleembodiment, the mineral coatings may be any suitable coating materialcontaining calcium and phosphate, such as hydroxyapatite,calcium-deficient carbonate-containing hydroxyapatite, tricalciumphosphate, amorphous calcium phosphate, octacalcium phosphate, dicalciumphosphate, calcium phosphate, and the like. The mineral coating may alsoinclude a plurality of layers having distinct dissolution profiles tocontrol dissolution order, kinetics and bioactive delivery properties.Under physiological conditions, the solubility of calcium phosphatematerials are as follows: amorphous calcium phosphate>dicalciumphosphate>octacalcium phosphate>tricalcium phosphate>hydroxyapatite.Thus, a plurality of various calcium phosphate layers can provide abroad range of dissolution patterns. Incorporation of blank layers(i.e., calcium phosphate layers not containing any bioactive agent) canprovide for delayed release. Also, the incorporation of layers havingdifferent concentrations of bioactive agent can provide for varyingrelease rates.

A bioactive agent can be associated with uncoated biocompatible materialforming the scaffold 40 and/or the mineral coated portions of thescaffold 40. Different release rates of the bioactive agent would bepossible from uncoated and coated areas of the scaffold 40. Whilevarious bioactive agents listed above are suitable for use with thescaffold 40, in one example embodiment, the bioactive agent is selectedfrom bone morphogenetic proteins, demineralized bone matrix, bone marrowaspirate, and mixtures thereof. Bone morphogenetic proteins have beenshown to be excellent at growing bone and powdered recombinant humanBMP-2 is available in certain commercial products. Demineralized bonematrix includes osteoinductive proteins (e.g., bone morphogeneticproteins), and can be used in a particle or fiber form. Bone marrowaspirate contains osteoprogenitor cells, and the patient's bone marrowcan be readily harvested with a needle. As used herein, a bioactiveagent is “associated” with the polymer and/or the coating if thebioactive agent is directly or indirectly, physically or chemicallybound to the polymer and/or the coating. A bioactive agent may bephysically bound to the polymer and/or the coating by entrapping,imbedding or otherwise containing a bioactive agent within the polymerand/or the coating network structure. A bioactive agent may bechemically bound to the polymer and/or the coating by way of a chemicalreaction wherein a bioactive agent is covalently or ionically bonded tothe polymer and/or the coating. Thus, various techniques for associatinga bioactive agent in or on the polymer and/or the coating arecontemplated herein.

The bioactive agent is present in amount that induces ossification orfibrous tissue growth depending on the effect desired. The amount ofbioactive agent included on uncoated and/or coated areas of the scaffold40 will depend on a variety of factors including the nature of thebioactive agent, the osteoinductive potential of the bioactive agent,and the nature of the carrier material (e.g., the biocompatible materialforming the scaffold 40 or the mineral coating on the scaffold 40).Investigations have shown that a 1-100 ng/ml concentration of BMP caninduce osteogenesis; and in one example, the BMP in the presentinvention can be released from the scaffold 40 in a time frame thatvaries from 10-50 days. Therefore, without intending to limit theinvention in any way, in the case of bone morphogenetic proteins, it iscontemplated that in one example a concentration of about 10-5000 ng ofbone morphogenetic protein per cm³ of material would be suitable forinducing ossification between the adjacent bones or adjacent bonesurfaces.

Various regions of the scaffold 40 can include the coatings andassociated bioactive agent. For example, the plates 45, 51 that aresecured to the opposed vertebrae can be coated with continuous coatingor islands of the coating and a bioactive agent associated with thecoating so that bone growth is induced, while interior sections of thescaffold may not include coatings and may include different associatedbioactive agents in order to promote growth of fibrous tissue. As anexemplary illustration, plates 45, 51 in FIG. 4 could include acontinuous mineral coating and associated bioactive agent so that bonefixation to the adjacent vertebra is induced, while the wavy fiberedmicrostructure 32 may include undifferentiated chondrocyte precursorcells from periosteum, mesenchymal stem cells from bone marrow,chondrocytes, sclerosing agents, angiogenesis activators, and/orangiogenesis inhibitors so fibrous growth is promoted in this region.

Preferably, the bioactive agents (e.g., bone morphogenetic proteins,chondrocytes) are associated with uncoated biocompatible materialforming the scaffold 40 and/or the mineral coated portions of thescaffold 40 prior to inserting the wavy fibered microstructure 32 in theintervertebral disc space. For example, a bone morphogenetic protein maybe chemically bonded (e.g., ionically or covalently bonded) to a calciumphosphate coating at a manufacturing site, or alternatively a bonemorphogenetic protein may be chemically bonded to the calcium phosphatecoating by a surgeon before and/or after implantation. The surgeon canreconstitute powdered bone morphogenetic protein with sterile water andapply the reconstituted powdered bone morphogenetic protein to thescaffold 40. Likewise, chondrocytes could be bonded to the wavy fiberedmicrostructure 32 by a surgeon, or at the manufacturing site.

Alternatively, fixation to the first upper vertebra and the adjacentsecond lower vertebra can be created as a keel riser structure, as shownin FIGS. 5A and 5B. The scaffold 60 of FIGS. 5A and 5B includes a wavyfibered microstructure 32 a having top projections 61 from a top surface62 of the scaffold 60 and bottom projections 63 from a bottom surface ofthe scaffold 60. When used in intervertebral disc repair, the wavyfibered microstructure 32 a of the scaffold 60 would be positioned inthe intervertebral space created by removal of the intervertebral discbetween adjacent vertebrae. The top projections 61 would assistattachment to a bottom surface of the first upper vertebra, and thebottom projections 63 would assist attachment to the top surface anadjacent second lower vertebra.

The fixation structures, the attached plate structure and/or keelstructure, will be porous polymers, ceramics and metals that may be madeas composites with the actual disk scaffolding. The final scaffoldingstructure will be created by Boolean intersection of the fixationstructures image design database with the scaffolding structure imagedesign database. The final result will be a designed, porous scaffoldingstructure that forms a composite with the designed, porous fixationstructures, as shown in FIG. 4 or FIGS. 5A and 5B.

For the osteochondral scaffolding, the same fixation design procedure isused. FIG. 6 shows a density map 70 for the tibial plateau where lines71, 72 mark the different density regions for mapping heterogeneousmicrostructure. In this case, microstructures similar to those designsin FIGS. 2A, 2B and 2C, including but not limited to the wavy fiberdesign 32 may be used to create functionally graded structures for theosteochondral scaffold. These designs are then substituted into densitymap 70 of FIG. 6 to create a scaffold design with desired shape andmicrostructure, along with fixation pegs. FIG. 7 shows an example finalosteochondral scaffold 80 with desired shape and microstructure. Thescaffold 80 includes a tibial plateau 82 having fixation pegs 83extending downward from a bottom surface 84 of the scaffold 80.Preferably, the tibial plateau 82 region is designed to includespherical or elliptical pores in order to enhance cartilage growth.Also, the tibial plateau 82 region may be designed to have a lowerelasticity than the pegs 83 to promote cartilage growth. The final fitof the osteochondral scaffold 80 in the tibial plateau 85 of a tibia 86is shown in FIG. 8.

The scaffold 80 can comprise a porous biocompatible and biodegradable(if desired) porous material selected from polymeric materials, metallicmaterials, ceramic materials and mixtures thereof. In one exampleembodiment, the scaffold 80 is formed from polycaprolactone, abiocompatible and biodegradable polymer. However, other polymers such aspolylactide, polyglycolide, poly(lactide-glycolide), poly(propylenefumarate), poly(caprolactone fumarate), polyethylene glycol, andpoly(glycolide-co-caprolactone) may be advantageous for forming thescaffold 80.

An osteoconductive mineral coating can formed on at least a portion ofthe scaffold 80 where bone growth is desired. Bioactive agents wouldalso be beneficial in the scaffold 80 of FIG. 7. For example, a bonemorphogenetic protein may be chemically bonded (e.g., ionically orcovalently bonded) to a calcium phosphate coating at the bottom surface84 of the scaffold 80 for fixation to the tibia 86, while chondrocytescould be bonded to the tibial plateau 82 for cartilage growth.

In addition to being used for porous osteochondral scaffolds, thecurrent designed microstructures could be used as bone interfaces formore traditional total joint replacements. In this case, a porousmicrostructure designed to have desired mechanical and mass transportproperties would be designed to cover a joint replacement surface. Thejoint structure could be scanned using CT methods and the designedmicrostructure would be combined using Boolean methods. FIG. 9 showssuch a combination for a simple solid stem 90 with a designed coatingmicrostructure 92. The stem simulates a hip stem with a designedmicrostructure as an interface for fixation of the stem to surroundingbone.

If it is desired to create a scaffolding to engineer a newintervertebral disc, then the fabrication materials may include acomposite of a degradable polymer for the structural scaffolding and ahydrogel interspersed within the designed scaffolding. A bioactive agentmay also be included in the scaffolding. The degradable polymer mayinclude one of the following, but is not limited to: (1)Polycaprolactone; (2) Polylactic Acid; (3) Polylactic-Polyglycolic AcidCo-polymer; (4) Polypropylene Fumarate; (5) Poly(glycerol-sebacate), and(6) Poly Octane Diol Citrate. The hydrogel may include, but is notlimited to: (1) Fibrin Gel; (2) Polyethylene Glycol (PEG); (3) CollagenI Gel; and (4) Collagen/Hyaluronic Acid Gel.

If it is desired to create an intervertebral fusion device, then thescaffolding material may, in addition to the degradable polymers listedabove, may also include, but is not limited to, the following: (1)Calcium Phosphate Ceramic; (2) Calcium Phosphate Ceramic/PolymerComposite; and (3) Titanium.

For an osteochondral scaffold, similar materials may be used to engineerthe cartilage component including: (1) Polycaprolactone; (2) PolylacticAcid; (3) Polylactic-Polyglycolic Acid Co-polymer; (4) PolypropyleneFumarate, (5) poly(glycerol-sebacate), and (6) Poly Octane Diol Citrate.The hydrogel may include, but is not limited to: (1) Fibrin Gel; (2)Polyethylene Glycol (PEG); (3) Collagen I Gel; and (4)Collagen/Hyaluronic Acid Gel.

For the bone portion of the osteochondral scaffold, the materials mayinclude polymer, ceramics or metals. Polymers may include, but are notlimited to: (1) Polycaprolactone; (2) Polylactic Acid; (3)Polylactic-Polyglycolic Acid Co-polymer; and (4) Polypropylene Fumarate.These polymers may be surface engineered to include a biomineralizedsurface layer to improve osteoconductivity using a technique such asthat described in U.S. Pat. No. 6,767,928, which is incorporated hereinby reference as if fully set forth herein. In addition, both ceramicsand metals may be used to fabricate the bone portion, including but notlimited to: (1) Calcium Phosphate Ceramic; (2) Calcium PhosphateCeramic/Polymer Composite; and (3) Titanium. The osteochondral scaffoldmay also include a bioactive agent in the bone and/or cartilage portion.

For the total joint replacement with a designed microstructureinterface, the materials may be those commonly used for jointreplacements including but not limited to: (1) Titanium Alloys such asTi6Al4V; (2) Chrome Cobalt Molybdenum Alloys; and (3) Stainless Steel.The joint replacement may also include a bioactive agent.

The invention may be used for biologic regeneration of an intervertebraldisc. Current attempts to resume partial or even full disc functionsinclude disc regeneration by applying the state-of-art tissueengineering strategies. One key principle to conduct such strategies isto generate two distinct anatomic regions on the designed scaffolds thatmake up the intervertebral disc (IVD) and culture correspondingparenchymal cells at the central region resembling nucleus pulposus (NP)and the peripheral region for annulus fibrosus (AF). However, theconcept has been only tested subcutaneously in a few studies. If theapproach would be applied in situ, one can imagine there will beinevitably critical hurdles that can hinder any successfulness of fullfunctional disc regeneration. The major concern of engineering fullfunctional disc is cell survival. It is known that disc tissue isavascular with very low cellular density only 1% to 2% of the tissuevolume. IVD cells, especially NP cells, rely highly on the nutrientsupply diffused through the cartilaginous endplates on the superior andinferior surfaces. When a discectomy is executed, the endplates areexposed, and the insertion of the scaffold may interfere with theendplates due to the non-physical contact. In addition, the interfacebetween the scaffold and the endplates may not be able to become fullyintegrated during neo-disc tissue formation. The situation will endangerthe implanted cells by starving them away from the diffused nutritionand may result in significant cell death and fail the full discregeneration.

As the alternative, the present invention proposes unified fibroustissue regeneration for disc replacement. Originated from the clinicalinvestigation, it is well known that some cases of interbody fusion candevelop into asymptomatic pseudarthrosis, which indicates a non-solid,fibrous union rather than solid bone fusion. The reason physicians tendto explain for this phenomenon is that it may be because sufficientamount of fibrous tissue formation occurs intervertebrally and itprovides sufficient stiffness to maintain the disc height, whilepreserving certain amount of motion without disturbing nerve roots.Moreover, it is speculated that with the formation of fibrous union,contact stress from body weight becomes more evenly distributed on thenew fibrous construct, which, very possibly, reduces the etiology ofaxial discogenic pain.

By applying the approach already described on engineering scaffolds, thepresent invention can design a scaffold with the same inherent disctissue properties to provide immediate support post-operatively. As ithas been proven that sclerosing agents induce scarring for fibrosis andtissue contraction, the present invention combines these agents toincrease fibrous tissue union in a controlled manner to confine the newfibrous tissue within the designed architecture. Any therapeuticproteins, growth factors, progenitor cells, and molecules/compounds, ifaiming at beneficiating fibrous tissue formation, can be also includedin our designed scaffold. Vehicles in gel forms or microspheres may alsobe associated with the usage of this invention as substantial componentsfor applying the proposed unified fibrous tissue regeneration for discreplacement.

Once the intervertebral scaffolding image-design dataset is created, itcan be automatically converted into a surface representation in .stlfile format (stereolithography triangular facet data). This makes itpossible to fabricate the intervertebral scaffolding from any type ofSolid Free-Form Fabrication (SFF) system using either direct or indirectmethods. The direct SFF methods include, but are not limited to: (1)Selective Laser Sintering (SLS); (2) Stereolithography (SLA); (3) FusedDeposition Modeling (FDM); and (4) Selective Laser Melting (SLM). Oneexample solid freeform fabrication method may be found in U.S. PatentApplication Publication No. 2003/0074096, which is incorporated hereinby reference as if fully set forth herein.

Indirect methods are based on casting biomaterials, such as those listedabove, into a mold created on a SFF system. In addition to the above SFFsystems, the molds may also be created on direct 3D printing systems,including those systems that print wax. The indirect methods describedin U.S. Patent Application Publication No. 2003/0006534 and U.S. Pat.No. 7,087,200 (which are both incorporated herein by reference as iffully set forth herein) may be used to make the disc scaffold.

The methodology of the invention has been implemented to make scaffoldsfor temporomandibular joint repair in a Yucatan Minipig model. Thedesign procedure involved taking a CT scan of the minipig, usingimage-based techniques to design and fabricate the scaffold, andsurgically implanting the scaffold. FIG. 10 shows the steps of anexample procedure for mandibular condyle engineering from image tofabricated scaffold. Note that this scaffold has features createduniquely from image-based design, including a wrap-around ramus collarthat allows surgical fixation, as shown with the screw holes.

Referring to FIG. 10, a spherical void architecture design 102 is chosenfor the cartilage (surface) region of the image based design. Anorthogonal strut architecture design 104 is chosen for the bone regionof the image based design. The microstructure designs 102, 104 may becreated using the image based design methods described in U.S. PatentApplication Publication No. 2003/0069718. The resulting CT scan imagesprovide the condyle shell anatomic external shape and design space forthe scaffold 110. These images are stored as density distribution withina voxel dataset. The method merges the anatomic and architecturedatabases (see arrows 112, 113, 114). The method converts the voxeldesign to a surface or wire frame geometry (see arrow 115). The methodfabricates the design scaffold from biomaterial using direct or indirect(casting) solid free form techniques (see arrow 116).

In addition, working prototypes have been built of a cervical discdesign with anterior fixation plate and designed microstructure. SeeFIG. 11. The scaffold 120 of FIG. 11 includes the wavy fiberedmicrostructure 32 in the correct anatomic shape for a naturalintervertebral disc. A top fixation plate 125 includes spaced apartfastener holes 146 a, (second hole not shown), and a top centralU-shaped cutaway section 147. A bottom fixation plate 151 includesspaced apart fastener holes 152 a, 152 b, and a bottom central invertedU-shaped cutaway section 153. The wavy fibered microstructure 32 isintegral with the fixation plates 125, 151. When used in intervertebraldisc repair, the wavy fibered microstructure 32 of the scaffold 120would be positioned in the intervertebral space created by removal ofthe intervertebral disc between adjacent vertebrae. Fasteners would beinserted in fastener holes 146 a, (second hole not shown), for anteriorattachment to a first upper vertebra, and fasteners would be inserted infastener holes 152 a, 152 b for anterior attachment to an adjacentsecond lower vertebra. The top end surface 154 of the wavy fiberedmicrostructure 32 would contact a lower surface of the first uppervertebra, and the opposite bottom end surface 155 of the wavy fiberedmicrostructure 32 would contact an upper surface of the second lowervertebra. The wavy fibered microstructure 32 thereby provides mechanicalload bearing support between the first upper vertebra and the secondlower vertebra. The plates 125, 151 may include throughholes to allowfluid into the interior spaces of the scaffold to minimize any problemsassociated with tissue blockage of fluid. Optionally, flaps (not shown)can be provided on the plates 125, 151 to prevent backing out of thefasteners (e.g., fixation screws). In one embodiment, the fixationscrews can be formed using the same biocompatible and biodegradablematerial with an osteoconductive mineral coating, and a bioactive agentassociated with the biodegradable material and/or the coating.

The scaffold 120 can comprise a porous biocompatible and biodegradable(if desired) porous material selected from polymeric materials, metallicmaterials, ceramic materials and mixtures thereof. In one exampleembodiment, the scaffold 120 is formed from polycaprolactone, abiocompatible and biodegradable polymer. However, other polymers such aspolylactide, polyglycolide, poly(lactide-glycolide), poly(propylenefumarate), poly(caprolactone fumarate), polyethylene glycol, andpoly(glycolide-co-caprolactone) may be advantageous for forming thescaffold 120.

The vertical dimensions of the wavy fibered microstructure 32 in FIG. 11can be adjusted accordingly for various different intervertebraldistances. Likewise, the horizontal length of the fixation plates 125,151 and their spatial relationship can be varied to ensure properlocation of the fastener holes 146 a, (second hole not shown), 152 a,152 b adjacent the first upper vertebra and the second lower vertebrafor securing the scaffold 120 to the first upper vertebra and the secondlower vertebra. By varying the dimensions of the wavy fiberedmicrostructure 32 and the fixation plates 125, 151 different sizescaffolds 120 can be provided for selection by a surgeon.

This disc scaffold 120 also has features created uniquely fromimage-based design, including plates 125, 151 that allow surgicalfixation, as shown with the fastener holes. Various regions of the discscaffold 120 can include the mineral coatings and associated bioactiveagent. For example, top and bottom end regions that are positioned nearthe opposed vertebrae can be coated with continuous or islands of thecoating and associated bioactive agent so that bone growth is induced,while interior sections of the disc may not include coatings andassociated bioactive agent in order to promote growth of fibrous tissue.

Because placement of the disc scaffold 120 of FIG. 11 may be performedusing a medical imaging device and techniques (e.g., fluoroscopicobservation), the disc scaffold 120 may further include at least onemarking including a tracer that provides enhanced visibility via themedical imaging device. For example, non-limiting examples of radiopaquematerials for enhanced visibility during fluoroscopy include bariumsulfate, tungsten, tantalum, zirconium, platinum, gold, silver,stainless steel, titanium, alloys thereof, and mixtures thereof.Radiopaque markings can be used as an alignment aid in verifying theproper positioning of the disc scaffold. Also, the scaffold 120 mayinclude a region of no material or radiolucent material such that theregion forms an imaging window for enhanced visibility through theimaging window via a medical imaging device.

Therefore, it can be seen that the invention provides a method ofdesigning an intervertebral body scaffolding with controlled elastic andpermeability properties that may mimic that natural function ofvertebral discs. The designed permeability will allow nutrients todiffuse into the disc to allow survival of delivered cells or cells thatmigrate into the disc. Disc scaffolding permeability could also bedesigned to mimic the permeability distribution of normal discs. Inaddition, with the wavy fibered microstructure, the disc scaffold couldexhibit nonlinear behavior similar to human intervertebral disc. Thiscapability is not seen in prior artificial discs, tissue engineereddiscs, or spine fusion approaches. Furthermore, the disc may befabricated as a composite material.

The invention also provides a method of designing an osteochondralscaffold design with a joint interface design. The invention includesthe ability to design effective mechanical and mass transport propertiesof the interface and the ability to fabricate these controlledmicrostructures. In addition, invention includes the ability to readilyfabricate adjunct surgical fixation based on anatomic features.

The invention also provides a method of designing a joint replacement.The invention provides methods and devices that stabilize a joint,promote fibrous tissue union of adjacent bones, and allow for motionbetween adjacent bones.

Although the invention has been described in considerable detail withreference to certain embodiments, one skilled in the art will appreciatethat the present invention can be practiced by other than the describedembodiments, which have been presented for purposes of illustration andnot of limitation. In particular, the methods and devices describedherein can used to promote fibrous union between any bone surfaces.Therefore, the scope of the appended claims should not be limited to thedescription of the embodiments contained herein.

1. An intervertebral disc repair and/or regeneration scaffoldcomprising: a central core shaped to approximate the nucleus pulposus ofa natural intervertebral disc, the central core having a first porousmicrostructure; and an outer annulus shaped to approximate the annulusfibrosus of a natural intervertebral disc, the outer annulus connectedto and surrounding the central core, the outer annulus having a secondporous microstructure, wherein the central core and the outer annulushave different permeability.
 2. The scaffold of claim 1, wherein thecentral core and the outer annulus have different elasticity.
 3. Thescaffold of claim 1, wherein the central core includes a bioactiveagent.
 4. The scaffold of claim 3, wherein the bioactive agent isselected from undifferentiated chondrocyte precursor cells fromperiosteum, mesenchymal stem cells from bone marrow, chondrocytes,sclerosing agents, angiogenesis activators, angiogenesis inhibitors, andmixtures thereof.
 5. The scaffold of claim 1, wherein the scaffold isformed from a biodegradable polymer.
 6. The scaffold of claim 1, whereinthe central core includes a biocompatible material.
 7. The scaffold ofclaim 1, wherein the central core includes a hydrogel.
 8. The scaffoldof claim 1, wherein the central core comprises wavy fibers.
 9. Thescaffold of claim 1, wherein the scaffold is formed from a materialselected from biodegradable polymers, biodegradable ceramics,non-biodegradable metals, non-biodegradable metal alloys, or mixturesthereof.
 10. The scaffold of claim 1, further comprising at least onemarking including a tracer that provides enhanced visibility via amedical imaging device.
 11. The scaffold of claim 1, further comprisingat least one radiopaque marking that provides enhanced visibility via afluoroscope.
 12. The scaffold of claim 1, wherein the scaffold includesa region of no material or radiolucent material such that the regionforms an imaging window for enhanced visibility through the imagingwindow via a medical imaging device.
 13. The scaffold of claim 1,wherein the scaffold includes at least one marking for alignment duringimplantation.
 14. The scaffold of claim 1, further comprising anosteoconductive mineral coating on at least a portion of the scaffold.15. The scaffold of claim 14, wherein the osteoconductive mineralcoating comprises a plurality of discrete mineral islands.
 16. Thescaffold of claim 14, wherein the osteoconductive mineral coatingcomprises a substantially homogeneous mineral coating.
 17. The scaffoldof claim 14, wherein the osteoconductive mineral coating comprises acalcium compound.
 18. The scaffold of claim 14, wherein theosteoconductive mineral coating comprises hydroxyapatite,calcium-deficient carbonate-containing hydroxyapatite, tricalciumphosphate, octacalcium phosphate, dicalcium phosphate, calciumphosphate, and mixtures thereof.
 19. The scaffold of claim 14, wherein abioactive agent is associated with the mineral coating.
 20. The scaffoldof claim 14, wherein the bioactive agent is selected from bonemorphogenetic proteins.